Diabetic enteropathy is a poorly understood disorder which causes significant morbidity, impairs glycemic control and is not adequately explained by vagal dysfunction and hyperglycemia. Our preliminary data, partly based on in vitro studies conducted by colleagues in this PPG, suggest that in addition to vagal dysfunction, an integrated neurohormonal axis comprising incretins (particularly GLP-1), disordered enteric, particularly nitrergic neurotransmission, and sympathetic dysfunction are critical to the pathophysiology of diabetic enteropathy, and provide novel therapeutic avenues for this disorder. Our SPECIFIC AIMS are to test the HYPOTHESES that:- (1) GLP-1 induced proximal gastric relaxation is mediated by enteric nitrergic neurons and does not involve extrinsic (i.e. vagus or sympathetic) nerves; (2) Medium-term administration of exogenous nitrates will restore disturbances of gastric emptying and accommodation in diabetic dyspepsia, irrespective of the presence of vagal neuropathy; and (3) alpha2 adrenoreceptor mediated sympathetic inhibition retards gastrointestinal transit in diabetics with constipation. Hypothesis 1 will be confirmed by demonstrating that the nitric oxide synthase inhibitor L-NMMA, but not the alpha2-antagonist yohimbine inhibits GLP-1 induced gastric accommodation in healthy subjects; validated canine models of extrinsic vagal and sympathetic denervation will confirm that the effects on GLP-1 on gastric accommodation are not mediated by extrinsic nerves. Hypothesis 2 will be tested by measuring the effect of acute (1 day) and medium-term (6-week) treatment with isosorbide mononitrate on gastric emptying in diabetics with dyspepsia with or without abdominal vagal neuropathy. For hypothesis 3, we will characterize dose-effects of yohimbine on colonic transit, followed by a medium-term (6-week p.o.) trial of yohimbine on colonic transit in diabetics with constipation. In addition to state-of-the-art assessments of gastrointestinal transit, 99mTc SPECT imaging of gastric accommodation and intra-luminal colonic motor activity, we also propose, based on encouraging preliminary data, to develop and validate a novel 3-D MR imaging sequence to visualize gastric accommodation, avoiding radiation exposure. We anticipate that these hypotheses-driven studies that directly apply insights from in vitro and in vivo studies to diabetic patients will improve our understanding of disordered mechanisms and provide novel therapies for diabetic enteropathy in humans.